Precise modulation of hepatic glucose metabolism is crucial during the fasting and feeding cycle and is controlled by the actions of circulating insulin and glucagon. The insulin-signaling pathway requires insulin receptor substrate 1 (IRS1) and IRS2, which are found to be dysregulated in diabetes and obesity. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a fasting-induced transcriptional coactivator. In nonalcoholic fatty liver disease and in patients with type 2 diabetes, low hepatic PGC1A levels are associated with insulin resistance. However, how PGC1A activity impacts the hepatic insulin-signaling pathway is still unclear. We used gain- and loss-of-function models in mouse primary hepatocytes and measured hepatocyte insulin response by gene and protein expression and ex vivo glucose production. We found that the PGC1A level determines the relative ratio of IRS1 and IRS2 in hepatocytes, impacting insulin receptor signaling via protein kinase B/AKT (AKT). PGC1A drove the expression of IRS2 downstream of glucagon signaling while simultaneously reducing IRS1 expression. We illustrate that glucagon- or PGC1A-induced IRS2 expression was dependent on cAMP Response Element Binding Protein activity and that this was essential for suppression of hepatocyte gluconeogenesis in response to insulin in vitro. We also show that increased hepatic PGC1A improves glucose homeostasis in vivo, revealing a counterregulatory role for PGC1A in repressing uncontrolled glucose production in response to insulin signaling. These data highlight a mechanism by which PGC1A plays dual roles in the control of gluconeogenesis during the fasting-to-fed transition through regulated balance between IRS1 and IRS2 expression.

The nervous system processes sensory information by relying on the precise coordination of neuronal networks and their specific synaptic firing patterns. In the spinal cord, disturbances to the firing pattern of the tonic firing parvalbumin (PV)-expressing inhibitory interneuron (PV neurons) disrupt the ability of the dorsal horn to integrate touch information and may result in pathological phenotypes. The parvalbumin protein (PVp) is a calcium (Ca2+)-binding protein that buffers the accumulation of Ca2+ following a train of action potential to allow for tonic firing. Here, we find that peripheral nerve injury causes a decrease in PVp expression in PV neurons and makes them transition from tonic to adaptive firing. We also show that reducing the expression of PVp causes otherwise healthy adult mice to develop mechanical allodynia and causes their PV neurons to lose their high frequency firing pattern. We show that this frequency adaptation is mediated by activation of SK channels on PV neurons. Further, we show their tonic firing can be partially restored after nerve injury by selectively inhibiting the SK2 channels of PV neurons. We also reveal that a decrease in the transcriptional coactivator, PGC-1α causes decrease PVp expression and the development of mechanical allodynia. By preventing the decrease in PVp expression before nerve injury, we were able to protect mice from developing mechanical allodynia. Our results indicate an essential role for PVp-mediated calcium buffering in PV neuron firing activity and the development of mechanical allodynia after nerve injury.